promoting C–C bond forming reactions in scCO2. We have
applied this system to the first example of polymer-supported
reactions in scCO2.
We thank the EPSRC, AstraZeneca, the Commission of the
EU (Brite-Euram Contract BRRT-CT98-5089 ‘RUCADI’) and
the Isaac Newton Trust, Cambridge for generous financial
support. We thank EPSRC for provision of the Swansea Mass
Spectrometry Service.
Scheme 1 Reagents and conditions: (i) 5 mol% Pd(OAc)2, 10 mol%
phosphine 1, NEt3, scCO2, 100 °C, 40 h. (ii) NaOMe, MeOH, THF.
Suzuki reaction was also successful (entries 2–4). The yields for
these reactions are not yet optimised.†
Both aryl iodides and bromides underwent the Suzuki
reaction, although lower yields were obtained with the less
reactive bromide coupling partners. A variety of different bases
were investigated and shown to be effective in scCO2.
Surprisingly these reactions proceeded effectively in the
presence of solid tetraalkylammonium acetate salts without
addition of any other base. Jeffrey has reported the use of
alkylammonium salts for the Heck reaction in conventional
solvents.14 In addition, Bannwarth reported the use of tetra-n-
butylammonium chloride in a Stille reaction in scCO2.10 We
have found in related cross coupling reactions that the acetate is
superior.15
Solid phase organic synthesis carried out on a substrate
bound to a solid, typically polymeric, support continues to be an
area of intense study. The application of solid phase synthesis to
palladium-catalysed reactions has been the subject of recent
reviews.16,17 Conducting reactions on a solid support provides
an attractive and practical method for clean and efficient
synthetic preparations, allowing convenient separation of
products from the reaction mixture and forming the basis of
combinatorial chemistry. Reactions using polymer supports
require the use of a solvent that will swell the polymer and
expose reactive sites. The ability of scCO2 to plasticise
polymers has been exploited in a number of applications
including polymer impregnation, formation of blends and
particle formation.18 We expected therefore that scCO2 would
provide a good swelling solvent for polymer supported
reagents, allowing access to reactive sites and reducing the
amount of excess reagent required to give acceptable cov-
erage.
We now report the successful application of solid supported
substrates for palladium catalysed Heck and Suzuki couplings
in scCO2. The first pilot reaction employed a catalytic system of
palladium acetate with the highly fluorinated phosphine
PhP(CH2CH2C6F13)2, 1 (Scheme 1).6 REM resin19 underwent a
Heck reaction with iodobenzene and the modified resin was
then cleaved under basic conditions to give (E)-methyl
cinnamate in 74% yield over the two steps.
After this initial success we then extended the palladium
acetate–P(t-Bu)3 catalytic system to substrates immobilised on
a polymer resin. The Suzuki reaction was applied to a
functionalised Merrifield resin and proceeded in good yield,
comparable to reactions off resin (Table 1, entries 5a and b). The
Heck reaction on REM resin19 gave a near-quantitative yield
(entry 6). These results clearly demonstrate the successful
application of the palladium-mediated cross-coupling method-
ology to a heterogeneous system, and form to our knowledge the
first example of the use of polymer supported synthesis in
scCO2.
Notes and references
† Typical procedure for the Suzuki reaction in supercritical carbon dioxide:
palladium(II) acetate, (11 mg, 0.05 mmol) and tolylboronic acid (204 mg,
1.5 mmol) were placed in a 10 cm3 stainless steel cell, which was taken into
a nitrogen atmosphere (glove-box) where tri-tert-butylphosphine (20 mg,
0.1 mmol) was added, and the cell was sealed, and removed from the glove-
box. Iodobenzene (0.204 g, 1 mmol) and N,N,NA,N'A-tetramethylhexane-
1,6-diamine (0.172 g, 1 mmol) were injected through the inlet port. The cell
was then connected to the CO2 line and charged with CO2 (99.9995%—fur-
ther purified over an Oxisorb® catalyst) to approximately 880 psi (volume
ca. 5 cm3 liquid carbon dioxide). The cell was heated to 100 °C and the
pressure was adjusted to 3000 psi by the addition of CO2. The reagents were
maintained at this temperature and pressure for 16 h and the cell was then
allowed to cool to room temperature. The contents of the cell were vented
into ethyl acetate (100 cm3), and once atmospheric pressure had been
reached the cell was opened and washed out with further ethyl acetate (20
cm3). The combined organic fractions were concentrated in vacuo to give
the crude product which was adsorbed onto a flash silica column using
CH2Cl2 and eluted with hexane to give a white crystalline solid (128 mg,
76%), mp 47–48 °C (lit.20 49–50 °C) dH (400 MHz; CDCl3) 7.59 (2 H, dd,
oA-Ph, J 7.8, 1.2 Hz), 7.51 (2H, d, m-Ar, J 8.1 Hz), 7.44 (2 H, dd, mA-Ph, J
7.8, 7.35 Hz), 7.33 (1 H, td, pA-Ph, J 7.35, 1.2 Hz), 7.26 (2H, d, o-Ar, J 8.1
Hz), 2.41 (3 H, s, Ar-CH3).
1 R. S. Oakes, A. A. Clifford and C. M. Rayner, J. Chem. Soc., Perkin
Trans. 1, 2001, 917.
2 J. A. Darr and M. Poliakoff, Chem. Rev., 1999, 99, 495.
3 P. G. Jessop and W. Leitner, Chemical Synthesis Using Supercritical
Fluids, Wiley-VCH, Weinheim, 1999.
4 I. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009.
5 A. Suzuki, J. Organomet. Chem., 1999, 576, 147.
6 M. A. Carroll and A. B. Holmes, Chem. Commun., 1998, 1395.
7 D. K. Morita, D. R. Pesiri, S. A. David, W. H. Glaze and W. Tumas,
Chem. Commun., 1998, 1397.
8 N. Shezad, R. S. Oakes, A. A. Clifford and C. M. Rayner, Tetrahedron
Lett., 1999, 40, 2221.
9 B. M. Bhanage, Y. Ikushima, M. Shirai and M. Arai, Tetrahedron Lett.,
1999, 40, 6247.
10 T. Osswald, S. Schneider, S. Wang and W. Bannwarth, Tetrahedron
Lett., 2001, 42, 2965.
11 A. F. Littke and G. C. Fu, J. Org. Chem., 1999, 64, 10.
12 A. F. Littke and G. C. Fu, J. Am. Chem. Soc., 2001, 123, 6989 and
references cited therein.
13 I. Bach and D. J. Cole-Hamilton, Chem. Commun., 1998, 1463.
14 T. Jeffrey, Tetrahedron, 1996, 30, 10113.
15 T. R. Early, R. S. Gordon, M. A. Carroll, A. B. Holmes, R. E. Shute and
I. F. McConvey, manuscript in preparation.
16 C. L. Kingsbury, S. J. Mehrman and J. M. Takacs, Curr. Org. Chem.,
1999, 3, 497.
17 R. Franzen, Can. J. Chem., 2000, 78, 957.
18 A. I. Cooper, J. Mater. Chem., 2000, 10, 207 and references cited
therein.
19 J. R. Morphy, Z. Rankovic and D. C. Rees, Tetrahedron Lett., 1996, 37,
In summary we have shown that the non-fluorinated
palladium acetate–P(t-Bu)3 catalyst system is highly active in
3209.
20 M. S. C. Rao and G. S. K. Rao, Synthesis, 1987, 231.
Chem. Commun., 2001, 1966–1967
1967